Objective: Systemic lupus erythematosus (SLE) is characterized by dysregulation of autoreactive lymphocytes and antigen presenting cells. Signaling through Toll-like receptor 9 (TLR9) (a mediator of innate immune responses) plays a role in activation of dendritic cells and autoreactive B cells. Thus, we asked whether TLR9 polymorphisms are associated with an increased risk of SLE.
Methods: DNA samples were obtained from more than 200 Japanese SLE patients (>4 American College of Rheumatology criteria for SLE) and controls. The genetic variations of TLR9 were detected by PCR followed by DNA sequencing. The promoter and enhancer activities of TLR9 were measured by luciferase reporter gene assay. The titers of anti-dsDNA antibodies in sera from control or TLR9-deficient mice were analyzed by ELISA.
Results: The G allele at position +1174 (located in intron 1 of TLR9) is closely associated with an increased risk of SLE (P = 0.029). Furthermore, SLE patients tend to have C allele at position -1486 (P=0.11). Both alleles downregulate TLR9 expression by reporter gene assay. TLR9-deficient mice under a C57BL/6 background possess higher titers of anti- dsDNA serum antibodies compared to control C57BL/6 mice.
Conclusions: These results indicate that the presence of the G allele at position +1174 of TLR9 predisposes humans to an increased risk of SLE. We speculate that TLR9 normally prevents the development of human SLE.
- toll-like receptors
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Supplementary figure legends
Supplementary Figure 1. The +1174 genotype and SLICC damage index and onset age
a) The SLICC damage index was scored in SLE patients (n=35) with TLR9 gene variations at the position of +1174 (A/A, A/G, G/G). Horizontal bar indicates the average score of each group. No statistical correlation between +1174 genotypes and SLICC damage score was found. (SLICC;Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index for Systemic Lupus Erythematosus ). b) The onset age of SLE patients (n=35) was compared among +1174 genotypes (A/A, A/G, G/G). Horizontal bar indicates the average onset age of each group. There was no statistical correlation between +1174 genotypes and disease onset.
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